Altered cofactor regulation with disease-associated p97/VCP mutations

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Dominant mutations in p97/VCP cause multisystem degenerative diseases.
• p97 disease mutants exhibit altered N-domain conformation, ATPase activity, and cofactor association.

Purpose of the Study:

• To identify how cofactors p37 and p47 regulate p97 ATPase activity.
• To understand the role of cofactor regulation in p97-associated disease pathogenesis.

Main Methods:

• Biochemical assays to measure p97 ATPase activity.
• Site-directed mutagenesis to alter p47 cofactor function.
• Analysis of cofactor binding and conformational changes in p97.

Main Results:

• p37 is identified as the first p97-activating cofactor, enhancing catalytic efficiency by 11-fold.
• p47 exhibits biphasic regulation of p97 ATPase activity.
• Deletion of amino acids 69-92 in p47 converts it to an activating cofactor.
• Disease mutants of p97 fail to be activated by p37 or p47.

Conclusions:

• Cofactors p37 and p47 play a critical role in controlling p97 ATPase activity.
• Cofactor binding induces conformational changes affecting p97 ATPase cycling.
• Impaired cofactor-regulated communication in disease mutants may contribute to pathogenesis.